BACE1 inhibitors

Abstract

The present invention provides a compound of formula I having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

The invention claimed is: 
     
       1. A compound of formula I, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of
 i) aryl, 
 ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-4 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-6 -alkyl, 
 iii) heteroaryl, and 
 iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, cyano-C 1-4 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-4 -alkoxy, C 2-6 -alkynyl and C 1-4 -alkyl; 
 
         R 2  is selected from the group consisting of
 i) hydrogen, 
 ii) C 1-4 -alkyl, and 
 iii) halogen; 
 
         R 3  is selected from the group consisting of
 i) C 1-6 -alkyl, and 
 ii) halogen-C 1-6 -alkyl, 
 
         R 4  is selected from the group consisting of
 i) halogen, and 
 ii) hydrogen, 
 
         R 5  is halogen-C 1-4 -alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound of formula I, of formula Ia-1 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of
 i) aryl, 
 ii) aryl substituted by 1-2 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-4 -alkyl, 
 iii) heteroaryl, and 
 iv) heteroaryl substituted by 1-2 substituents individually selected from amino, cyano, cyano-C 1-6 -alkyl, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl, C 2-6 -alkynyl-C 1-6 -alkoxy, C 2-6 -alkynyl and C 1-6 -alkyl; and 
 
         R 3  is selected from the group consisting of
 i) C 1-6 -alkyl, and 
 ii) halogen-C 1-6 -alkyl, 
 
         R 4  is selected from the group consisting of
 i) halogen, and 
 ii) hydrogen, 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. The compound according to  claim 1 , wherein R 1  is heteroaryl substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C 1-6 -alkoxy, halogen-C 1-6 -alkyl, C 1-6 -alkoxy and C 1-6 -alkyl. 
     
     
       4. The compound according to  claim 1 , wherein R 1  is heteroaryl substituted by 1-2 substituents individually selected from amino and cyano. 
     
     
       5. The compound according to  claim 1 , wherein R 1  is pyridinyl, 1H-pyrazolyl or pyrazinyl. 
     
     
       6. The compound according to  claim 1 , wherein R 1  is pyridinyl or pyrazinyl. 
     
     
       7. The compound according to  claim 1 , wherein R 1  is pyridinyl. 
     
     
       8. The compound according to  claim 1 , wherein R 1  is 3,5-dichloro-pyridinyl, 3-chloro-5-cyano-pyridinyl, 3-chloro-5-trifluoromethyl-pyridinyl, 4-chloro-1-(difluoromethyl)-1H-pyrazolyl, 5-(difluoromethyl)-pyrazinyl, 5-(fluoromethoxy)pyridinyl, 5-cyano-3-methyl-pyridinyl, 5-cyano-pyridinyl, 5-methoxy-pyrazinyl or 5-methoxy-pyridinyl. 
     
     
       9. The compound according to  claim 1 , wherein R 1  is 5-cyano-pyridine-2-yl. 
     
     
       10. The compound according to  claim 1 , wherein R 2  is halogen. 
     
     
       11. The compound according to  claim 1 , wherein R 2  is F. 
     
     
       12. The compound according to  claim 1 , wherein R 3  is C 1-6 -alkyl. 
     
     
       13. The compound according to  claim 1 , wherein R 3  is methyl. 
     
     
       14. The compound according to  claim 1 , wherein R 4  is halogen. 
     
     
       15. The compound according to  claim 1 , wherein R 4  is fluoro. 
     
     
       16. The compound according to  claim 1 , wherein R 4  is hydrogen. 
     
     
       17. The compound according to  claim 1 , wherein R 5  is fluoro-C 1-6 -alkyl. 
     
     
       18. The compound according to  claim 1 , wherein R 5  is trifluoromethyl. 
     
     
       19. The compound according to  claim 1  selected from the group consisting of:
 N-(6-((4R,5R,6R)-2-amino-5-fluoro-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide, 
 N-(6-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-cyanopicolinamide, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(trifluoromethyl)picolinamide 2,2,2-trifluoroacetate, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypyrazine-2-carboxamide 2,2,2-trifluoroacetate, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyano-3-methylpicolinamide 2,2,2-trifluoroacetate, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-methoxypicolinamide 2,2,2-trifluoroacetate, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide 2,2,2-trifluoroacetate, 
 N-(6-(4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-(difluoromethyl)pyrazine-2-carboxamide 2,2,2-trifluoroacetate, 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3,5-dichloropicolinamide 2,2,2-trifluoroacetate, 
 N-(6 ((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-(fluoromethoxy)picolinamide 2,2,2-trifluoroacetate, and 
 N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-chloropyridin-2-yl)-5-cyanopicolinamide, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       20. The compound according to  claim 1 , wherein said compound is N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-5-cyanopicolinamide or a pharmaceutically acceptable salt thereof. 
     
     
       21. A process for preparing a compound according to  claim 1 , comprising the step of reacting a compound of formula XI′ with a compound of formula XII′ 
       
         
           
           
               
               
           
         
         to form a compound of formula I, wherein R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 1  and X is an amino protecting group. 
       
     
     
       22. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance. 
     
     
       23. A method for treating a disease or disorder characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  to a human being or animal in need thereof. 
     
     
       24. A method for treating Alzheimer's disease, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  to a human being or animal in need thereof.